Injectable bulking compositions

ABSTRACT

According to an aspect of the invention, injectable bulking compositions are provided which contain the following: (a) fibers that are configured to prevent migration to locations in the body remote from the injection site, for example, because they have a minimum length that is sufficiently large to prevent migration of the fibers and/or because they have surface features that stimulate host tissue response to lock the fibers in position and (b) a carrier in an amount effective to render the composition injectable.

STATEMENT OF RELATED APPLICATIONS

This application is a continuation of co-pending U.S. patent applicationSer. No. 11/125,297, filed May 9, 2008, entitled “Injectable BulkingCompositions” and is incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

The present invention relates to injectable bulking compositions formedical and cosmetic applications, among others.

BACKGROUND OF THE INVENTION

Urinary incontinence, vesicourethral reflux, fecal incontinence,intrinsic sphincter deficiency (ISD) and gastro-esophageal refluxdisease, are examples of disorders, among others, that have responded totreatments with augmentative materials. In addition, it is known to useaugmentative materials for aesthetic improvement, including improvementof skin contour.

For instance, a common method for treating patients with urinaryincontinence is via periurethral injection of a bulking material. Onesuch bulking composition is a paste known commercially as POLYTEF orURETHRIN. This paste is comprised of a fifty-fifty (50-50) by weightmixture of a glycerin liquid with polytetrafluoroethylene (PTFE)particles and is sold by DuPont. Over a period of time, the glycerindissipates into the body and is then metabolized or eliminated, reducingthe effective volume of the bulking material. Consequently, to achievethe desired result, the surgeon can overcompensate for the anticipatedloss of bulking material by injecting a significantly larger amount ofmaterial than is initially required. However, the eventual dissipationof the glycerin complicates the surgeon's ability to gauge theappropriate amount of bulking material to inject. Furthermore, inextreme circumstances, such overcompensation can lead to completeclosure of the urethra, which could put the patient into temporaryurinary retention. As a result, the surgeon may ultimately not injectenough bulking mixture into the patient, leading to the need for asecond or even a third procedure to inject additional material.

An alternative to PTFE paste is a collagen gel such as CONTIGEN,available from C R Bard. The collagen gel is injected and forms afibrous mass of tissue around the augmentation site. This fibrous mass,created by the collagen injection, however, also dissipates over timeand is eventually eliminated by the patient's body. As a result,additional injections are periodically required.

Yet another alternative is a hard particle suspension. One suchcommercially available product is DURASPHERE available from CarbonMedical Technologies. These hard particles, carbon coated zirconiumbeads, are injected in a beta-glucan carrier. The beta-glucan iseliminated by the patient's body over time. Moreover, in many cases,migration of the particles after administration appears to reduce thebulking effect of the particles over time. As a result, additionalinjections may be required.

In this regard, methods of injecting bulking agents commonly require theplacement of a needle at a treatment region, for example,peri-urethrally or transperineally. The bulking agent is injected into aplurality of locations, assisted by visual aids, causing the urethrallining to coapt. In cases where additional applications of bulking agentare required, the newly added bulking agent may need to be injected at ahigher pressure than the pressure at which the initial bulking agent wasinjected.

From the above, it is apparent that there is a need for bulkingcompositions which do not require supplemental injections or whichrequire less frequent supplemental injections.

SUMMARY OF THE INVENTION

These and other challenges are addressed by the present invention.

According to an aspect of the invention, injectable bulking compositionsare provided which contain: (a) fibers that are configured to preventmigration to locations in the body remote from the injection site, forexample, because they have a minimum length that is sufficiently largeto prevent migration of the fibers and/or because they have surfacefeatures that stimulate host tissue response to lock the fibers inposition, and (b) a carrier in an amount effective to render thecomposition injectable.

An advantage of the present invention is that bulking compositions areprovided, which promote tissue growth subsequent to administration. Thiseffect can be used, for example, to make up for the loss ofbiodegradable bulking materials, to reduce migration of biostablebulking materials, to increase the compliance of the body of thebulking, and so forth.

In addition, because the bulking compositions of the present inventioncomprise fibers, an oriented structure is created upon administration(e.g., due to the passage of the fibers through a narrow lumen, such asa needle, which encourages them into a parallel formation), which inturn encourages oriented tissue, such as scar tissue or collagen growth.

These and other aspects, embodiments and advantages of the presentinvention will become immediately apparent to those of ordinary skill inthe art upon review of the Detailed Description and Claims to follow.

DETAILED DESCRIPTION OF THE INVENTION

According to an aspect of the present invention, injectable bulkingcompositions are provided, which comprise (a) fibers that are configuredto prevent migration to locations in the body remote from the injectionsite, for example, because they have a minimum length that issufficiently large to prevent migration of the fibers and/or becausethey have surface features that stimulate host tissue response to lockthe fibers in position and (b) a carrier for the fibers, which isprovided in an amount effective to render the composition injectable.The fiber size is also beneficially of sufficient length such that localmigration at the point of injection is minimized.

Applications for bulking agents in accordance with the invention includethe treatment urinary incontinence, vesicourethral reflux, fecalincontinence, intrinsic sphincter deficiency, and aesthetic shaping(e.g., treatment of skin contour deficiencies), among others. Theinjectable compositions of the invention can be introduced into thesubject via a variety routes, including, for example, transabdominal,transperineal, transcutaneous, transvascular, transurethral,periurethral, transureteral, transoral, and transrectal routes ofinsertion. Other routes of injection may also be suitable, depending onthe location of the tissue to be treated. Where urethral bulking is thegoal, periurethral or transperineal routes are typically used. Subjects(also referred to as patients) include vertebrate subjects, typicallymammalian subjects, and more typically human subjects.

As used herein, a “fiber” is an elongated particle having a length thatis at least 10 times longer than the greatest width of the particle,typically at least 20 times longer, at least 50 times longer, at least100 times longer, or even more. For instance, in the case of acylindrical fiber, the length is at least 10 times the diameter, whereasin the case of a ribbon-shaped fiber, the length is at least 10 timesthe width of the ribbon, and so forth. Fibers in accordance with thepresent invention typically have lengths ranging from 0.5 to 5000microns and a maximum width ranging from 0.05 to 500 microns, and theymore typically have a length ranging from 1 to 1000 microns and amaximum width ranging from 0.1 to 10 microns. Fibers within this sizerange are available commercially from a wide variety of sources, or theycan be formed using a number of known fiber forming techniques.

Without wishing to be bound by theory, it is believed that, due to theirelongate nature, the fibers within the compositions of the presentinvention are injected into tissue in an oriented (e.g., substantiallyparallel) manner, thereby creating an oriented scaffold which acts as aguide for cell migration, cell attachment, cell growth and/or tissuedeposition (e.g., collagen fiber deposition). In some embodiments, thesurfaces of the fibers are textured to enhance these processes.

The compositions of the invention typically contain from 30 to 90 wt %fibers, more typically from 50 to 80 wt % fibers.

Materials useful for forming fibers in accordance with the presentinvention include inorganic and organic materials, which can be naturalor synthetic, and can be biostable or biodisintegrable (e.g.,biodegradable). By “biodisintegrable” is meant that the materialundergoes dissolution, degradation (i.e., bond cleavage, such ashydrolysis) and/or other disintegration process upon injection into thebody, although such disintegration processes can take place over anumber of months or even years. Conversely, by “biostable” is meant thatthe material remains substantially intact upon injection into the body.

Suitable inorganic materials for forming fibers in accordance with thepresent invention can be selected from the following: silica-basedmaterials, sometimes referred to as glass ceramics (e.g., silica andbioglass); calcium-phosphate-based materials (e.g., hydroxyapatite);metal oxides, including aluminum oxides and transition metal oxides(e.g., oxides of titanium, zirconium, hafnium, tantalum, molybdenum,tungsten, rhenium and iridium); metals; and carbon based ceramic-likematerials such as substantially pure carbon, silicon carbide and carbonnitride.

Suitable organic materials for forming fibers in accordance with thepresent invention can be selected from the following materials, many ofwhich are polymers: polymers and copolymers of vinyl monomers includingpolyvinyl alcohols, polyvinyl ketones, polyvinylcarbazoles, polyvinylesters such as polyvinyl acetates, polyvinyl halides such as polyvinylchlorides, ethylene-vinyl acetate copolymers (EVA), polyvinylidenechlorides, polyvinyl ethers such as polyvinyl methyl ethers,polyvinylpyrrolidone, vinyl aromatics such as polystyrenes,styrene-maleic anhydride copolymers, vinyl-aromatic-olefin copolymers,including styrene-butadiene copolymers, styrene-ethylene-butylenecopolymers (e.g., a polystyrene-polyethylene/butylene-polystyrene (SEBS)copolymer, available as Kraton® G series polymers), styrene-isoprenecopolymers (e.g., polystyrene-polyisoprene-polystyrene),acrylonitrile-styrene copolymers, acrylonitrile-butadiene-styrenecopolymers, styrene-butadiene copolymers and styrene-isobutylenecopolymers (e.g., polyisobutylene-polystyrene andpolystyrene-polyisobutylene-polystyrene block copolymers such as thosedisclosed in U.S. Pat. No. 6,545,097 to Pinchuk); silicone polymers andcopolymers; poly(carboxylic acid) polymers and copolymers includingpolyacrylic and polymethacrylic acid, and salts thereof,ethylene-methacrylic acid copolymers and ethylene-acrylic acidcopolymers, where some of the acid groups can be neutralized with eitherzinc or sodium ions (commonly known as ionomers); acrylate andmethacrylate polymers and copolymers (e.g., n-butyl methacrylate);acetal polymers and copolymers; cellulosic polymers and copolymers,including cellulose acetates, cellulose nitrates, cellulose propionates,cellulose acetate butyrates, cellophanes, rayons, rayon triacetates, andcellulose ethers such as carboxymethyl celluloses and hydroxyalkylcelluloses; polyoxymethylene polymers and copolymers; polyimide polymersand copolymers such as polyether block imides, polyamidimides,polyesterimides, and polyetherimides; polyamide polymers and copolymersincluding nylon 6,6, nylon 12, polycaprolactams, polyacrylamides andpolyether block amides; polysulfone polymers and copolymers includingpolyarylsulfones and polyethersulfones; resins including alkyd resins,phenolic resins, urea resins, melamine resins, epoxy resins, allylresins and epoxide resins; polycarbonates; polyacrylonitriles;polybenzimidazoles; polyesters including polyethylene terephthalates andaliphatic polyester polymers and copolymers of alpha-hydroxy acids suchas polylactide (including d-, 1- and meso forms), polyglycolide andpoly(lactide-co-glycolide), epsilon-caprolactone,poly(lactide-co-caprolactone), polyhydroxybutyrate, polyhydroxyvalerate,poly(para-dioxanone), polymers of trimethylene carbonate (and its alkylderivatives), 1,4-dioxepan-2-one, 1,5-dioxepan-2-one, and6,6-dimethyl-1,4-dioxan-2-one; polyether polymers and copolymersincluding polyarylethers such as polyphenylene ethers, polyetherketones, polyether ether ketones, and polyalkyl oxides such aspolyethylene oxide (PEO) and polypropylene oxide; polyphenylenesulfides; polyisocyanates; polyolefin polymers and copolymers, includingpolyalkylenes such as polypropylenes, polyethylenes (low and highdensity, low and high molecular weight), polybutylenes (such aspolybut-1-ene and polyisobutylene), polyolefin elastomers (e.g.,santoprene), ethylene propylene diene monomer (EPDM) rubbers,poly-4-methyl-pen-1-enes, ethylene-alpha-olefin copolymers,ethylene-methyl methacrylate copolymers and ethylene-vinyl acetatecopolymers; fluorinated polymers and copolymers, includingpolytetrafluoroethylenes (PTFE),poly(tetrafluoroethylene-co-hexafluoropropene) (FEP), modifiedethylene-tetrafluoroethylene copolymers (ETFE), and polyvinylidenefluorides (PVDF); thermoplastic polyurethanes (TPU); elastomers such aselastomeric polyurethanes and polyurethane copolymers (including blockand random copolymers that are polyether based, polyester based,polycarbonate based, aliphatic based, aromatic based and mixturesthereof; examples of commercially available polyurethane copolymersinclude Bionate®, Carbothane®, Tecoflex®, Tecothane®, Tecophilic®,Tecoplast®, Pellethane®, Chronothane® and Chronoflex®); p-xylylenepolymers; polyiminocarbonates; copoly(ether-esters) such as polyethyleneoxide-polylactic acid copolymers; polyphosphazines; polyalkyleneoxalates; polyoxaamides and polyoxaesters (including those containingamines and/or amido groups); polyorthoesters; waxes, such as paraffinwax; biopolymers, such as polypeptides, proteins and polysaccharides andfatty acids (and esters thereof), including collagen, dextranomerfibrin, fibrinogen, elastin, chitosan, gelatin, starch,glycosaminoglycans such as hyaluronic acid, as well as mixtures andfurther copolymers of the preceding.

Polymers for forming fibers for use in the present invention includehomopolymers and copolymers (including alternating, random, statistical,gradient and block copolymers), which may be cyclic, linear or branched(e.g., the polymers may have star, comb or dendritic branchedarchitecture). They may be natural or synthetic, they may bethermoplastic or thermosetting, and so forth.

Materials, such as the inorganic and organic materials described above,can constitute the entirety of the fibers or only a portion of thefibers (e.g., constituting one component of a blend of materials,constituting a coating layer over a substrate, constituting a substratebeneath a coating layer, and so forth).

The surface characteristics that stimulate host tissue response to lockthe fibers in position include surface features, such as roughness andmicroscopic patterns, as well as coatings of therapeutic agents. Thesurface roughness and microscopic patterns will promote cell adhesionand therefore enhance host tissue response, whereas therapeutic agentsmay chemically or biologically promote certain types of desired hosttissue responses, for example, promoting quick tissue ingrowth.

To render them injectable, fibers such as those described above aregenerally admixed with a carrier, which in turn can be formed using oneor more carrier species. The carrier typically includes one or moreliquid species, for example, water, one or more liquid organic species(e.g., glycerin or other alcohols), or a mixture of water and one ormore liquid organic species. Additional species such as alginate,beta-glucan, cellulose, collagen, and so forth, may also be providedwithin the carrier to improve the properties of the carrier, forexample, to improve carrier viscosity, carrier lubricity, etc.

In certain embodiments, the bulking compositions of the presentinvention are provided with one or more optional therapeutic agents.Therapeutic agents include small molecule therapeutics, biopolymertherapeutics (e.g., proteins, DNA encoding proteins, polysaccharides,and so forth) as well as cells. Therapeutic agents may be includedsingly or in combination.

These optional therapeutic agents may be included in the bulkingcompositions in amounts effective to achieve a variety of purposes,including promotion of tissue growth, thereby allowing them to increasethe long term (i.e., a period of at least 6 months) tissue bulkingeffect of the compositions, promotion of fibroblast attachment,enhancement of cellular migration to the injection site, promotion oforganized soft tissue formation, and combinations of these effects.

For example, where the fibers within the bulking compositions of theinvention are biodisintegrable, the optional therapeutic agents can beused to increase tissue bulk to compensate for the disintegration of thefibers. In this connection, it is noted that certain biodisintegrablepolymers, such as polylactide, polyglycolide, andpoly(lactide-co-glycolide), among others, produce inflammation as theydegrade due to pro-inflammatory breakdown products, which leads tobulking in the form of scar tissue formation. The rate and degree ofbiodisintegrable polymer breakdown can depend upon a number of factorsincluding monomer content (e.g., choice of monomer or ratio of monomers,if a copolymer), degree of crystallinity, polymer architecture, exposedsurface area, and so forth.

Where the fibers within the bulking composition are biostable, thefibers, along with any optional therapeutic agents, can work in tandemto provide effective bulking. Moreover, tissue growth may also be usefulto lock the fibers into place, thereby reducing or preventing migrationof the same within the tissue.

The one or more optional therapeutic agents can be provided in thecompositions of the invention in a number of ways, for example, blendedwith the fibers in the compositions, provided as coatings on the fibers,provided within matrices that correspond to the fibers or portions ofthe fibers (e.g., within coatings on the fibers), and so forth.

A range of therapeutic agent loadings can be used in conjunction withthe above dosage forms, with the effective amount of loading beingreadily determined by those of ordinary skill in the art and ultimatelydepending, for example, upon the nature of the therapeutic agent, thetissue into which the dosage forms are introduced, the presence of othercomponents in the dosage form, and so forth.

Therapeutic agents for use in conjunction with the present inventioninclude agents that promote proliferation of soft tissue, including thefollowing: connective tissue (e.g., fibrous connective tissue forstructural bulking, adipose tissue for cosmetic bulking, etc.), muscletissue (e.g., skeletal muscle for tendon repair), nervous tissue (e.g.,to attach damaged nerves to one another), and so forth. Frequently, thiswill involve migration, attachment and/or proliferation of various cellsincluding the following: connective tissue cells such as fibroblasts,adipocytes, macrophages, lymphocytes, mast cells; muscle cells such asskeletal muscle fibers (cells), cardiac muscle cells, and smooth musclecells; nerve cells such as peripheral ganglion cells and Schwann cells;epithelial tissue cells such as squamous epithelial cells, cuboidialepithelial cells, columnar epithelial cells, pseudostratified columnarepithelial cells, and transitional epithelial cells; and progenitorcells which mature into cells such as those above, such as totipotent,pluripotent, multipotent, and progenitor stem cells.

Hence, therapeutic agents that can be administered in accordance withthe present invention include those that promote migration, attachmentand/or growth of various cells, as well as the cells themselves or theirprogenitors, preferably derived from the subject to be treated.Therapeutic agents include drugs, growth factors, hormones, stem cells,and combinations thereof, among many others.

Specific beneficial therapeutic agents for the practice of the presentinvention include those that promote collagen production, such asproinflammatory agents and sclerosing agents.

Suitable proinflammatory agents can be selected, for example, fromendotoxins, cytokines, chemokines, prostaglandins, lipid mediators, andother mitogens. Specific examples of known proinflammatory agents fromwhich suitable proinflammatory agents can be selected include thefollowing: growth factors such as platelet derived growth factor (PDGF),fibroblast growth factor (FGF), transforming growth factor (such asTGF-alpha and TGF-beta), epidermal growth factor (EGF), insulinlikegrowth factor (IGF), interleukins such as IL-1-(alpha or beta), IL-8,IL-4, IL6, IL-10 and IL-13, tumor necrosis factor (TNF) such asTNF-alpha, interferons such as INF-gamma, macrophage inflammatoryprotein-2 (MIP-2), leukotrienes such as leukotriene B4 (LTB4),granulocyte macrophage-colony stimulating factor (GM-CSF),cyclooxygenase-1, cyclooxygenase-2, macrophage chemotactic protein(MCP), inducible nitric oxide synthetase, macrophage inflammatoryprotein, tissue factor, phosphotyrosine phosphates, N-formyl peptidessuch as formyl-Met-Leu-Phe (fMLP), second mitochondria-derived activatorof caspase (sMAC), activated complement fragments (C5a, C3a), phorbolester (TPA), superoxide, hydrogen peroxide, zymosan, bacteriallipopolysaccharide, chitin, imiquimod, and carrageenan, as well asmixtures thereof.

Sclerosing agents are agents that irritate tissue causing it sclerose orscar. However, due to the presence of fibers in the compositions of thepresent invention, the promoted scar tissue tends to be more organized,compared to typical bulking materials. This organization increases thecompliance of the new tissue. Consequently, the new bulking becomes morereadily adopted as natural host tissue.

Suitable sclerosing agents for the practice of the invention can beselected, for example, from the following (which list is not necessarilyexclusive of the pro-inflammatory list set forth above): inorganicmaterials such as talc, aluminum hydroxide (e.g., in slurry form),sodium hydroxide, silver nitrate and hypertonic saline, as well asorganic compounds, including alcohols such as ethanol (e.g., 50% toabsolute), acetic acid, trifluoroacetic acid, formaldehyde, dextrose,polyethylene glycol ethers (e.g., polidocanol, also known as laureth 9,polyethylene glycol (9) monododecyl ether, andhydroxypolyethoxydodecane), tetracycline, oxytetracycline, doxycycline,bleomycin, triamcinolone, minocycline, vincristine, iophendylate,tribenoside, sodium tetradecyl sulfate, sodium morrhuate, diatrizoatemeglumine, prolamine diatrizoate, alkyl cyanoacrylates such asN-butyl-2-cyanoactyalte and methyl 2-cyanoacrylate, ethanolamine,ethanolamine oleate, bacterial preparations (e.g., corynebacterium andstreptococcal preparations such as picibanil) and mixtures of the same,for instance, TES (mixture of 1% tetradecyl sulfate, 32% ethanol, and0.3% normal saline) and alcoholic solutions of zein (e.g., Ethibloc,which contains zein, alcohol, oleum papaveris, propylene glycol, and acontrast medium), and ethanol/trifluoroacetic acid mixtures, amongothers.

Note that in some cases, the therapeutic agents can also function ascarriers or as imaging contrast agents, which will now be discussed.

Non-invasive imaging is a valuable diagnostic tool. For example, imagingguidance, either internal or external, can be used to determine thelocation of the bulking agent that is introduced. Consequently, thecompositions of the present invention also optionally contain aneffective amount of one or more imaging contrast agents (i.e.,substances that enhance the image produced by medical diagnosticequipment). Among currently available contrast agents are magneticresonance imaging (MRI) contrast agents, ultrasonic imaging contrastagents, x-ray fluoroscopy contrast agents, nuclear medicine contrastagents, and others.

For example, x-ray based fluoroscopy is a diagnostic imaging techniquethat allows real-time patient monitoring of motion within a patient. Tobe fluoroscopically visible, devices and/or compositions are typicallyrendered more absorptive of x-rays than the surrounding tissue (e.g.,radiopaque materials). In various embodiments of the invention, this isaccomplished by the use of contrast agents. Examples of contrast agentsfor use in connection with x-ray fluoroscopy include metals, metal saltsand oxides (particularly bismuth salts and oxides), and iodinatedcompounds. More specific examples of such contrast agents includetungsten, platinum, tantalum, iridium, gold, or other dense metal,barium sulfate, bismuth subcarbonate, bismuth trioxide, bismuthoxychloride, metrizamide, iopamidol, iothalamate sodium, iodomidesodium, and meglumine

Ultrasound and magnetic resonance imaging can provide two- and/orthree-dimensional images of a portion of the body. Ultrasound and MRIare advantageous, inter alia, because they do not expose the patient ormedical practitioner to harmful radiation and can provide detailedimages of the observed area.

Ultrasound uses high frequency sound waves to create an image of livingtissue. A sound signal is sent out, and the reflected ultrasonic energy,or “echoes,” used to create the image. Ultrasound imaging contrastagents are materials that enhance the image produced by ultrasoundequipment. Ultrasonic imaging contrast agents introduced into thecompositions of the present invention can be, for example, echogenic(i.e., materials that result in an increase in the reflected ultrasonicenergy) or echolucent (i.e., materials that result in a decrease in thereflected ultrasonic energy). Suitable ultrasonic imaging contrastagents for use in connection with the present invention include solidparticles ranging from about 0.01 to 50 microns in largest dimension(e.g., the diameter, where spherical particles are utilized), moretypically about 0.5 to 20 microns. Both inorganic and organic particlescan be used. Examples include microparticles/microspheres of calciumcarbonate, hydroxyapatite, silica, poly(lactic acid), and poly(glycolicacid). Microbubbles can also be used as ultrasonic imaging contrastagents, as is known in the imaging art.

Magnetic resonance imaging (MRI) produces images by differentiatingdetectable magnetic species in the portion of the body being imaged. Inthe case of 1H MRI, the detectable species are protons (hydrogennuclei). In order to enhance the differentiation of detectable speciesin the area of interest from those in the surrounding environment,imaging contrast agents are often employed. These agents alter themagnetic environment of the detectable protons in the area of interestrelative to that of protons in the surrounding environment and, thereby,allow for enhanced contrast and better images of the area of interest.For contrast-enhanced MRI, it is desirable that the contrast agent havea large magnetic moment, with a relatively long electronic relaxationtime. Based upon these criteria, contrast agents such as Gd(III), Mn(II)and Fe(III) have been employed. Gadolinium(III) has the largest magneticmoment among these three and is, therefore, a widely-used paramagneticspecies to enhance contrast in MRI. Chelates of paramagnetic ions suchas Gd-DTPA (gadolinium ion chelated with the liganddiethylenetriaminepentaacetic acid) have been employed as MRI contrastagents. Chelation of the gadolinium or other paramagnetic ion isbelieved to reduce the toxicity of the paramagnetic metal by renderingit more biocompatible, and can assist in localizing the distribution ofthe contrast agent to the area of interest. Further information can befound, for example, in U.S. Patent Application No. 20030100830 entitled“Implantable or insertable medical devices visible under magneticresonance imaging,” the disclosure of which is incorporated herein byreference.

Although various embodiments are specifically illustrated and describedherein, it will be appreciated that modifications and variations of thepresent invention are covered by the above teachings and are within thepurview of the appended claims without departing from the spirit andintended scope of the invention.

1. An injectable bulking composition comprising: (a) inorganic fibersthat are configured to prevent migration of the inorganic fibers tolocations in the body remote from the injection site, and (b) a carrierin an amount effective to render the composition injectable.
 2. Theinjectable bulking composition of claim 1, wherein the majority of theinorganic fibers have a length that is at least 20 times longer than thegreatest width of the fiber.
 3. The injectable bulking composition ofclaim 1, wherein the majority of the inorganic fibers have a length thatis at least 50 times longer than the greatest width of the fiber.
 4. Theinjectable bulking composition of claim 1, wherein the compositioncomprises biostable inorganic fibers.
 5. The injectable bulkingcomposition of claim 1, wherein the composition comprisesbiodisintegrable inorganic fibers.
 6. (canceled)
 7. The injectablebulking composition of claim 1, wherein the inorganic fibers comprise amaterial selected from ceramics, silicon oxide, carbon, silicon carbide,and calcium-phosphate.
 8. The injectable bulking composition of claim 1,wherein the composition further comprises organic fibers.
 9. Theinjectable bulking composition of claim 1, wherein the compositionfurther comprises polymeric fibers.
 10. The injectable bulkingcomposition of claim 9, wherein the polymeric fibers comprise a polymerselected from poly(vinyl alcohol) homopolymers and copolymers,poly(lactide) homopolymers and copolymers and ethylene-vinyl acetatecopolymers.
 11. The injectable bulking composition of claim 1, furthercomprising a therapeutic agent in an amount effective to increase thelong term tissue bulking effect of said composition, to increasefibroblast attachment, to attract cellular migration to the injectionsite, to promote the formation of organized soft tissue, or acombination of these effects.
 12. The injectable bulking composition ofclaim 11, wherein said therapeutic agent comprises cells.
 13. Theinjectable bulking composition of claim 11, wherein said therapeuticagent comprises cells selected from stem cells, fibroblast cells, andcardiac muscle cells.
 14. The injectable bulking composition of claim11, wherein said therapeutic agent comprises a proinflammatory agent.15. The injectable bulking composition of claim 11, wherein saidtherapeutic agent comprises a sclerosing agent.
 16. The injectablebulking composition of claim 11, wherein said therapeutic agent isselected from growth factors and hormones.
 17. The injectable bulkingcomposition of claim 1, wherein said composition contains from 50 to 80wt % fibers.
 18. The injectable bulking composition of claim 1, whereina majority of said fibers have a maximum length of 1000 microns or less.19. The injectable bulking composition of claim 1, wherein said fibershave a length that is sufficiently large to prevent said migration. 20.The injectable bulking composition of claim 1, wherein said fibers havesurface features that stimulate host tissue response so as to preventsaid migration.
 21. A method of treating urinary incontinence,comprising administering an effective amount of the composition of claim1 to a subject's urethra.
 22. A method of cosmetic bulking, comprisingadministering a cosmetically effective amount of the composition ofclaim 1 to a subject.